Clinical Pharmacokinetics of the Androgen Receptor Inhibitor Darolutamide in Healthy Subjects and Patients with Hepatic or Renal Impairment.

BACKGROUND: Darolutamide is a second-generation androgen receptor inhibitor approved for the treatment of nonmetastatic castration-resistant prostate cancer at a dosage of 600 mg orally twice daily. OBJECTIVE: We aimed to fully characterize the pharmacokinetic profile of darolutamide, its diastereomers, and its main active metabolite, keto-darolutamide. METHODS: Single-dose and multiple-dose pharmacokinetics of 14C-labeled and non-labeled darolutamide were evaluated in healthy subjects and patients with hepatic or renal impairment. RESULTS: Following darolutamide oral tablet administration, peak plasma concentrations were reached 4-6 h after dosing. Darolutamide elimination was characterized by a half-life of 13 h. Steady state was reached after approximately 2 days of twice-daily dosing. Pharmacokinetics of the diastereomers and keto-darolutamide followed similar trends to the parent compound. Darolutamide absorption from the tablet was lower than from the oral solution; tablet absolute bioavailability was ~30% in the fasted state but improved to 60-75% when given with food. The unbound fraction of darolutamide in plasma was 7.8%. The administered 1:1 ratio of the diastereomers (S,R)-darolutamide and (S,S)-darolutamide changed to ~1:6 in plasma following multiple dosing. Similar exposure and diastereomer ratios after single and multiple dosing indicate time-independent (no autoinduction) linear pharmacokinetics. Darolutamide exposure increased in patients with moderate hepatic or severe renal impairment vs healthy subjects; dose adaptation at treatment initiation should be considered in these patients. CONCLUSIONS: Darolutamide 600 mg twice daily demonstrates predictable linear pharmacokinetics and sustainably high plasma concentrations, suggesting the potential for constant inhibition of the androgen receptor signaling pathway. CLINICAL TRIALS REGISTRATION: NCT02418650, NCT02894385, NCT02671097.

Metabolism and Mass Balance of the Novel Nonsteroidal Androgen Receptor Inhibitor Darolutamide in Humans.

The biotransformation and excretion of darolutamide were investigated in a phase I study. Six healthy male volunteers received a single dose of 300 mg 14C-darolutamide as an oral solution in the fasted state. Plasma, urine, and feces samples were analyzed for mass balance evaluation by liquid scintillation counting (LSC). Metabolite profiling and identification were determined using liquid chromatography mass-spectrometry with off-line radioactivity detection using LSC. Complete mass balance was achieved, with mean radioactivity recovery of 95.9% within 168 hours (63.4% in urine, 32.4% in feces). The administered 1:1 ratio of (S,R)- and (S,S)-darolutamide changed to approximately 1:5, respectively, in plasma. Darolutamide and the oxidation product, keto-darolutamide, were the only components quantifiable by LSC in plasma, accounting for 87.4% of total radioactivity, with a 2.1-fold higher plasma exposure for keto-darolutamide. Aside from darolutamide, the most prominent metabolites in urine were O-glucoronide (M-7a/b) and N-glucuronide (M-15a/b), as well as pyrazole sulfates (M-29, M-24) and glucuronides (M-21, M-22) resulting from oxidative cleavage of the parent. The darolutamide diastereomers were mainly detected in feces. In vitro assays showed that darolutamide metabolism involves a complex interplay between oxidation and reduction, as well as glucuronidation. Interconversion of the diastereomers involves oxidation to keto-darolutamide, primarily mediated by CYP3A4, followed by reduction predominantly catalyzed by cytosolic reductase(s), with aldo-keto reductase 1C3 playing the major role. The latter reaction showed stereoselectivity with preferential formation of (S,S)-darolutamide. SIGNIFICANCE STATEMENT: The metabolism and excretion of darolutamide in humans revealed that oxidation (CYP3A4) and glucuronidation (UGT1A9, UGT1A1) were the main metabolic routes of elimination. Direct excretion also contributed to overall clearance. The two pharmacologically equipotent diastereomers of darolutamide interconvert primarily via oxidation to the active metabolite keto-darolutamide, followed by reduction predominantly by cytosolic reductase(s). The latter reaction showed stereoselectivity with preferential formation of (S,S)-darolutamide. Data indicate a low drug-drug interaction potential of darolutamide with inducers or inhibitors of metabolizing enzymes.

Pharmacokinetics of Darolutamide, its Diastereomers and Active Metabolite in the Mouse: Response to Saini NK et al. (2020).

BACKGROUND: Saini et al. recently investigated the pharmacokinetics of darolutamide and its diastereomers in vitro and in vivo in Balb/c mice, reporting higher levels of (S,S)-darolutamide than (S,R)-darolutamide following intravenous or oral dosing, and interconversion of (S,R)-darolutamide to (S,S)-darolutamide. OBJECTIVE: To present our in vitro and in vivo studies of darolutamide pharmacokinetics in mice, which contrast with the findings of Saini et al. Methods: Nude male Balb/c mice were orally dosed for 7 days with 25, 50, or 100 mg/kg of darolutamide twice daily. Pharmacokinetic parameters in plasma and tissue samples were assessed by liquid chromatography-tandem mass spectrometry. Metabolism and interconversion of darolutamide and its diastereomers were investigated in cryopreserved Balb/c mouse hepatocytes. Protein binding was determined in plasma samples by equilibrium dialysis. RESULTS: On day 7, Cmax was reached 30 min after the last dose. Rapid formation and greater exposure of keto-darolutamide versus darolutamide were observed. Plasma exposure of (S,R)-darolutamide was 3-5-fold higher than that of (S,S)-darolutamide. The fraction of unbound keto-darolutamide was almost 6-fold lower than for darolutamide. In mouse hepatocytes, the conversion of (S,S)- to (S,R)-darolutamide was observed, but the conversion of (S,R)- to (S,S)-darolutamide was not detectable. Back-formation of keto-darolutamide to both diastereomers occurred at low levels. CONCLUSION: The darolutamide diastereomer ratio changes upon administration in mice and other species due to interconversion through keto-darolutamide. This is not considered clinically relevant since both diastereomers and keto- darolutamide are pharmacologically similar in vitro. Based on the high protein binding of keto-darolutamide, its contribution in vivo in humans is considered low.

Predicting the effect of prandial stage and particle size on absorption of ODM-204.

The prediction of absorption properties plays a key role in formulation development when the compound under development shows poor solubility and its absorption is therefore presumed to be solubility limited. In our work, we combined and compared data obtained from in vitro dissolution tests, transit intestinal model studies (TIM-1) and physiologically based pharmacokinetic modelling. Our aim was to determine the ability of these methods to predict performance of poorly soluble lipophilic weak base in vivo. The validity of the predictive methods was evaluated against the in vivo clinical pharmacokinetic (PK) data obtained after administration of the first test formulation, T1. The aim of our study was to utilize the models in evaluating absorption properties of the second test formulation, T2, which has not yet been clinically administered. The compound in the studies was ODM-204, which is a novel, orally administered, investigational, nonsteroidal dual inhibitor of CYP17A1 and androgen receptor. Owing to its physicochemical properties ODM-204 is prone to low or variable bioavailability. The models examined provided congruent data on dose dependent absorption, food effect at a dose of 200 mg and on the effect of API (active pharmaceutical ingredient) particle size on absorption. Our study shows that the predictive tools of in vitro dissolution, TIM-1 system and the PBPK (physiologically based pharmacokinetic) simulation, showed predictive power of different mechanisms of bioavailability and together provided valuable information for decision making.

ODM-204, a Novel Dual Inhibitor of CYP17A1 and Androgen Receptor: Early Results from Phase I Dose Escalation in Men with Castration-resistant Prostate Cancer.

BACKGROUND: Most prostate cancer patients develop castration-resistant prostate cancer (CRPC) after androgen deprivation therapy treatment. CRPC growth is mediated mostly by androgen receptor signalling driven by primary androgens synthesised largely by the CYP17A1 enzyme. OBJECTIVE: To evaluate the safety profile and dose-limiting toxicities of ODM-204. DESIGN, SETTING, AND PARTICIPANTS: In this open, uncontrolled, nonrandomised, multicentre, tolerability and pharmacokinetic first-in-man phase I dose escalation study, patients with metastatic CRPC were randomised to receive ODM-204 in sequential cohorts of five dose levels (ie, 50, 100, 200, 300, and 500mg twice daily) concomitantly with prednisone. INTERVENTION: ODM-204, a novel, orally administered, investigational, nonsteroidal dual inhibitor of CYP17A1 and androgen receptor. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: ODM-204 plasma concentrations, serum testosterone, and prostate-specific antigen (PSA) levels were evaluated and imaging of lesions was performed. RESULTS AND LIMITATIONS: Of the 23 patients enrolled into the study, 60.9% experienced mild adverse effects considered to be related to the study treatment, which were fatigue, increased/decreased appetite, nausea, asthenia, diarrhoea, and weight decrease. ODM-204 area under the curve (AUC0-12) values increased dose dependently until the 300mg dose. The AUC was lower on day 8 after repeated dosing compared with day 1 from the 200mg dose upwards. Decreases in testosterone levels were seen with ODM-204 treatment confirming androgen deprivation. Of the patients, 13% also demonstrated a >50% decrease in PSA at week 12 and continued ODM-204 treatment for over a year. CONCLUSIONS: ODM-204 was well tolerated up to the highest evaluated dose. There were decreases in both testosterone and PSA levels, suggesting preliminary antitumour activity in the treatment of CRPC. The pharmacokinetic properties of the molecule, however, prevent further development. PATIENT SUMMARY: This study looked at the safety of ODM-204, a novel dual inhibitor of CYP17A1 and the androgen receptor, in castration-resistant prostate cancer patients. ODM-204 treatment was found to be well tolerated, and it also reduced both serum testosterone and prostate-specific antigen levels, but the properties of the molecule prevent further development.

Pharmacokinetics, Antitumor Activity, and Safety of ODM-201 in Patients with Chemotherapy-naive Metastatic Castration-resistant Prostate Cancer: An Open-label Phase 1 Study.

BACKGROUND: ODM-201 is a novel second-generation androgen receptor inhibitor for the treatment of metastatic castration-resistant prostate cancer (mCRPC). OBJECTIVE: To evaluate the pharmacokinetics of ODM-201 tablet products and preliminary long-term safety, tolerability, and antitumor activity of ODM-201 in chemotherapy-naive men with mCRPC. DESIGN, SETTING, AND PARTICIPANTS: Thirty patients were enrolled in this open-label phase 1 trial. Patients received a single 600-mg dose of ODM-201 in capsules with food and one 600-mg dose of ODM-201 tablet product (TabA or TabB) with food and in the fasted state in a random order. In the extension, patients received 600mg twice daily ODM-201 taken with food in capsules. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We analyzed the pharmacokinetics of ODM-201 tablet formulations. Safety and tolerability were assessed until disease progression or an intolerable adverse event (AE). Antitumor activity was assessed by prostate-specific antigen (PSA) levels and imaging. RESULTS AND LIMITATIONS: The capsule:TabA ratio of area under the concentration-time curve from time zero to the last sample at 48h was 1.06 (90% confidence interval [CI], 0.91-1.24); the capsule:TabB ratio was 0.97 (90% CI, 0.82-1.14). At week 12, 25 of 30 patients (83%) had a PSA response (≥50% reduction from baseline). Median time to radiographic progression was 66 wk (95% CI, 41-79). Most common AEs were fatigue (n=4 [13%]) and nausea (n=4 [13%]). CONCLUSIONS: The study showed that the tablet formulation of ODM-201 had similar pharmacokinetics compared with the capsule. Treatment with a 600-mg twice daily dose of ODM-201 provided anticancer activity and was well tolerated in men with chemotherapy-naive mCRPC. PATIENT SUMMARY: The findings of this study showed that ODM-201 is well tolerated and provided antitumor activity in chemotherapy-naive patients with metastatic castration-resistant prostate cancer (mCRPC) and that the 300-mg tablet formulation can be used in further clinical studies. A phase 3 trial with ODM-201 600mg twice daily in patients with non-mCRPC is ongoing.

Discovery of ODM-201, a new-generation androgen receptor inhibitor targeting resistance mechanisms to androgen signaling-directed prostate cancer therapies.

Activation of androgen receptor (AR) is crucial for prostate cancer growth. Remarkably, also castration-resistant prostate cancer (CRPC) is dependent on functional AR, and several mechanisms have been proposed to explain the addiction. Known causes of CRPC include gene amplification and overexpression as well as point mutations of AR. We report here the pharmacological profile of ODM-201, a novel AR inhibitor that showed significant antitumor activity and a favorable safety profile in phase 1/2 studies in men with CRPC. ODM-201 is a full and high-affinity AR antagonist that, similar to second-generation antiandrogens enzalutamide and ARN-509, inhibits testosterone-induced nuclear translocation of AR. Importantly, ODM-201 also blocks the activity of the tested mutant ARs arising in response to antiandrogen therapies, including the F876L mutation that confers resistance to enzalutamide and ARN-509. In addition, ODM-201 reduces the growth of AR-overexpressing VCaP prostate cancer cells both in vitro and in a castration-resistant VCaP xenograft model. In contrast to other antiandrogens, ODM-201 shows negligible brain penetrance and does not increase serum testosterone levels in mice. In conclusion, ODM-201 is a potent AR inhibitor that overcomes resistance to AR-targeted therapies by antagonizing both overexpressed and mutated ARs. ODM-201 is currently in a phase 3 trial in CRPC.